Abstract The prevalence of Alzheimer's disease (AD), the most common form of dementia, is expected to triple to 13 million in the United States by the year 2050. Almost two-thirds with AD are women. The etiology of AD and Alzheimer's disease-related dementias (ADRD) is still not well understood. Recent evidence indicates that endogenous sex hormones may influence cognitive impairment, as a precursor to AD and ADRD. However, existing epidemiologic studies reported mixed results. Importantly, all studies conducted to date measured hormones in postmenopausal women, mostly > 65 years of age. While mechanistic studies suggested that endogenous sex hormones affect cognition starting during the pre- and perinatal period and through subsequent activating effects during adult life, epidemiologic studies with circulating sex hormones measured earlier in life are lacking. In addition, studies on other hormone-related biomarkers such as Anti-Mllerian hormone, a reliable predictor of ovarian reserve and age at menopause which has been related to AD, are limited. The New York University Women's Health Study (NYUWHS), funded by the NCI (5UM1CA182934), is a prospective cohort study with 14,274 healthy women recruited in 1985?1991. Notably, approximately 47% of women were 35-50 years of age at baseline, and serum samples were collected from all women at baseline. As these women are now 62-85 years of age, the NYUWHS presents a unique opportunity to study novel biomarkers in premenopausal period that are predictive of AD and ADRD. Leveraging the resources of biospecimens, existing infrastructure for follow-up that is funded by NCI, and data on lifestyle factors, reproductive factors, and biomarkers, we propose to: 1) conduct a two-stage telephone-based assessment following a validated protocol in 3,000 women premenopausal at baseline and identify women with cognitive impairment/probable dementia; and 2) conduct a case-control study to assess the association between premenopausal sex hormones and cognitive impairment. We will interview participants, using a validated two- stage telephone-based assessment consisting of the Telephone Interview of Cognitive Status-modified (TICSm) and proxies, using the Telephone Dementia Questionnaire (TDQ). We will measure circulating sex hormones in 200 cases of cognitive impairment/probable dementia and 400 matched controls. Studies on biomarkers measured at middle age in relation to cognitive impairment may provide data for screening and prevention programs for AD and ADRD according to the risk profile of the individual woman. The proposed aims will also provide resources and stimulate additional research activities on AD and ADRD leveraging the strengths of the cohort including long follow-up, availability of biospecimens, and nearly complete ascertainment of cancer status.